Abstract The incidence of clinical depression among glioma patients is greater than patients dealing with any other tumor type, including other brain cancers and metastatic lesions to the brain. One major regulator of mood and depression is the neurotransmitter, serotonin. Depression is associated with a decrease in the availability of serotonin and is commonly treated with a class of drugs called selective serotonin re-uptake inhibitors or SSRIs. SSRIs work by interfering with the proteins used by cells to capture and internalize serotonin, thereby maintaining higher levels of available serotonin and prolonging its anti-depressive effects. Under normal, non-cancerous conditions, serotonin also serves as a powerful stimulator of cell division and regulates the behavior of normal brain stem cells. One factor that contributes to the overwhelming lethality of high-grade gliomas (such as glioblastoma, or GBM) is the emergence of cancer stem cells (CSCs). CSCs invade extensively throughout the brain, resist chemotherapy and radiation treatment, and drive tumor recurrence. I have demonstrated that serotonin is also a powerful driver of GBM CSC proliferation. Serotonin-expressing neurons innervate GBM tumors and GBM CSCs express a variety of receptor proteins that capture serotonin and use that binding to drive cell division. For this proposal I will be testing the hypothesis that serotonin drives the proliferation and expansion of the CSC pool in GBM, resulting in enrichment of treatment-refractory CSCs and accelerating disease progression. This hypothesis will be tested in two experimental aims. Aim 1 will test the hypothesis that serotonin drives GBM progression and CSC maintenance. Aim 2 will test the hypothesis that SSRIs expand the CSC pool and accelerates GBM progression. The results of this work may reveal that GBM-associated depression results from tumor cells syphoning endogenous serotonin to drive their own self-renewal and proliferation. These data may also provide evidence that GBM treatment is undermined by using SSRIs to manage GBM-associated depression. Such results could have a major impact on the symptomatic management of GBM patients.